Macrolide antibacterial agents are widely used to treat and prevent bacterial infections. However, the discovery of bacterial strains which have resistance or insufficient susceptibility to macrolide antibacterial agents has promoted the development of compounds with modified or improved profiles of antibiotic activity. One such class of compounds is azalides, which includes azithromycin, described in U.S. Pat. Nos. 4,474,768 and 4,517,359. Azalides are macrolide antibacterial agents with a ring structure similar to the erythronolide A or B, however azalides possess a substituted or unsubstituted nitrogen moiety at the 9a position as illustrated in the following structure:
The potential for azalides to display modified or improved profiles for antibiotic activity has spawned extensive research to identify additional azalide derivatives with enhanced clinical properties. The following are examples of current efforts in azalide research:
PCT Application WO98/56801, published Dec. 17, 1998 discloses a series of 9a-(N-(alkyl))-azalide erythromycin A derivatives and a series of 9a-(N-(alkyl))-azalide 6-O-methylerythomycin A derivatives;
PCT Application WO98/56802, published Dec. 17, 1998 discloses a series of 9a-(N—(H))-azalide erythromycin A derivatives and a series of 9a-(N—(H))-azalide 6-O-methyl erythromycin A derivatives;
PCT Application WO99/00124, published Jan. 7, 1999 and PCT Application WO99/00125, published Jan. 7, 1999 disclose a series of 9a-(N—(Rn))-azalide 3-thioxo erythromycin A derivatives and a series of 9a-(N—(Rn))-azalide 6-O-methyl 3-oxo erythromycin A derivatives, wherein Rn is an optionally substituted alkyl or heteroalkyl; and
U.S. Pat. No. 5,686,587 discloses a synthesis of azithromycin comprising introducing a 9a-(N(H))-moiety to erythromycin A by oxime formation, Beckmann rearrangement, reduction, and methylation.
Additional disclosures delineating 15-membered azalide derivatives include, but are not limited to: PCT Application No. WO001/14397 (2001); PCT Application No. WO03/042228 (2003); PCT Application No. WO02/12260 (2002); U.S. Pat. No. 6,110,965 (2000); European Application No. 0 283 05 5 (1990); PCT Application No. WO99/20639 (1999); PCT Application No. WO02/055531 (2002); PCT Application No. WO93/13116 (1993); and commonly-assigned U.S. application Ser. No. 10/397,923 (filed Mar. 26, 2003) and Ser. No. 10/464,188 (filed Jun. 18, 2003).
PCT Application WO 03/095466 A1, published Nov. 20, 2003 and PCT Application WO 03/097659 A1, published Nov. 27, 2003 disclose a series of bicyclic erythromycin derivatives.